The goal of this project is to isolate and identify a diabetes susceptibility gene in NOD which may regulate development of diabetogenic T cells. Dr. Mc Duffie has produced a diabetes-resistant congenic-recombinant mouse strain, designated NOD.D-R2, which appears to carry a highly penetrant diabetes resistant gene on chromosome 4. Transfer of T cells from young, non-diabetic NOD donors to neonatal NOD.D-R2 mice overrides the protective phenotype and produces florid insulitis and overt diabetes. These results strongly suggest that the elements of the NOD environment required for activating diabetogenic effector cells are intact and that the beta-cells from these mice are susceptible to inflammatory damage. It also suggests that NOD.D-R2 mice lack a population of T cells which can cause pancreatic beta cell damage. In preliminary data, Dr. Mc Duffie presents results that tentatively map the position of this gene to a 2 cM region of chromosome 4. Dr. Mc Duffie has 4 specific aims: 1) to determine the role of immunocytes and hematopoietic precursors in the expression of the NOD.D-R2 phenotype by transfer of purified cell populations into NOD.scid recipients. These studies will utilize adoptive transfer technology to provide information about the immunologic changes mediated by this gene on the autoimmune susceptibility of NOD. 2) to confirm the mode of inheritance and phenotype conferred by the NOD.D-R2 gene via backcross studies with diabetes-prone (NOD) mice. This experiment will establish the penetrance of this gene which will be a key parameter for an appropriate interpretation of the fine mapping studies proposed in Specific Aim 3. 3) to develop a physical map of the NOD.D-R2 gene region. These studies will involve fine mapping the position of the gene to 1.0 cM via phenotypic analysis of congenic recombinants from a cross with NOD, and the production of a YAC/BAC contig across this interval in collaboration with Bruce Birren at MIT. 4) to identify the gene which controls the NOD.D-R2 phenotype. This aim will involve experiments performed in collaboration with Dr. Birren which will lead to the identification of the gene responsible for diabetes resistance in the NOD.D-R2. The long-term goals of these studies are to characterize the genetic basis for susceptibility to IDD in the NOD strain. In addition to NOD.D-R2, Dr. Mc Duffie has two other strains with interesting phenotypes which she hopes to expand these studies to these strains in the future.